Association between HLA-C alleles and COVID-19 severity in a pilot study with a Spanish Mediterranean Caucasian cohort

Abstract

The clinical presentations of COVID-19 may range from an asymptomatic or mild infection to a critical or fatal disease. Several host factors such as elderly age, male gender, and previous comorbidities seem to be involved in the most severe outcomes, but also an impaired immune response that causes a hyperinflammatory state but is unable to clear the infection. In order to get further understanding about this impaired immune response, we aimed to determine the association of specific HLA alleles with different clinical presentations of COVID-19. Therefore, we analyzed HLA Class I and II, as well as KIR gene sequences, in 72 individuals with Spanish Mediterranean Caucasian ethnicity who presented mild, severe, or critical COVID-19, according to their clinical characteristics and management. This cohort was recruited in Madrid (Spain) during the first and second pandemic waves between April and October 2020. There were no significant differences in HLA-A or HLA-B alleles among groups. However, despite the small sample size, we found that HLA-C alleles from group C1 HLA-C*08:02, -C*12:03, or -C*16:01 were more frequently associated in individuals with mild COVID-19 (43.8%) than in individuals with severe (8.3%; p = 0.0030; pc = 0.033) and critical (16.1%; p = 0.0014; pc = 0.0154) disease. C1 alleles are supposed to be highly efficient to present peptides to T cells, and HLA-C*12:03 may present a high number of verified epitopes from abundant SARS-CoV-2 proteins M, N, and S, thereby being allegedly able to trigger an efficient antiviral response. On the contrary, C2 alleles are usually poorly expressed on the cell surface due to low association with β2-microglobulin (β2M) and peptides, which may impede the adequate formation of stable HLA-C/β2M/peptide heterotrimers. Consequently, this pilot study described significant differences in the presence of specific HLA-C1 alleles in individuals with different clinical presentations of COVID-19, thereby suggesting that HLA haplotyping could be valuable to get further understanding in the underlying mechanisms of the impaired immune response during critical COVID-19.

HLA‐A*11:01 and HLA‐C*04:01 are associated with severe COVID‐19

“…Additionally, the association of HLA‐C*04:01 was described in another previous study but, in this case, only in advanced age 39 . Additionally, Vigon et al found an association between HLA‐C alleles classified as C2, such as HLA‐C*0401 , especially in homozygosis, and disease severity, probably due to its lower capacity to present viral peptides in a stable form 35 . Although other studies did not found any association, 6,40,41 the sample size of SCOURGE supports the possibility of a firm association of these HLA class I alleles in the evolution of COVID‐19.…”

“…39 Additionally, Vigon et al found an association between HLA-C alleles classified as C2, such as HLA-C*0401, especially in homozygosis, and disease severity, probably due to its lower capacity to present viral peptides in a stable form. 35 Although other studies did not found any association, 6,40,41 the sample size of SCOURGE supports the possibility of a firm association of these HLA class I alleles in the evolution of COVID-19. One study published recently showed a strong association of HLA-B*15:01 with asymptomatic disease, 42 but this was not the case in our study.…”

“…We hypothesize that HLA‐B*14:02 could have a similar role in SARS‐CoV‐2 infection and could be associated with a faster viral clearance through the presentation of a particular viral peptide that elicits a more effective response. In a small study in a Spanish population, HLA‐C alleles from Group C1, such as HLA‐C*08:02 , were associated with mild disease 35 . However, in the Sardinian population, the haplotype HLA‐A*30:02, C*08:02 was associated with higher susceptibility 36 .…”

“…In a small study in a Spanish population, HLA-C alleles from Group C1, such as HLA-C*08:02, were associated with mild disease. 35 However, in the Sardinian population, the haplotype HLA-A*30:02, C*08:02 was associated with higher susceptibility. 36 Obviously, further research in independent studies is required to confirm this assertion and to be replicated in other populations.…”

Tools for Etiologic Diagnosis of Drug-Induced Allergic Conditions

“…The standard positive threshold that is empirically adopted for positive results is more than 5% CD63+ basophils [ 152 , 153 ]. The BAT can also be considered positive if a two-fold increase in the stimulation index (SI) is observed.…”